SUMMARY Therapeutic immune checkpoint blocking antibodies and oncogene-targeted chemical inhibitors have revolutionized the treatment landscape for cancers, and now provide real hope to patients with advanced disease. However, while some patients will experience benefit, others will not respond at all ? a dilemma that is intimately linked to the genetic composition of the tumors. Identification of the molecular processes that enable, as well as preclude, positive responses to such therapies are urgently needed, and are likely to identify rational combinatorial approaches that will improve outcome. For immune checkpoint inhibitor therapies, evidence has accumulated to suggest that the mutational burden in the patients' cancer, through an increased frequency of neoantigen peptides, causes immunogenicity. In order to grow, such antigenic tumors must develop mechanisms that enable them to evade immune-mediated destruction, which makes these tumors vulnerable to immune checkpoint therapies that reverses tumor immune evasion. From our ongoing studies on how melanoma cells elude the efficacy of oncogene-targeted therapies, we have identified an immunosuppressive molecule whose expression levels are directly linked to the tumors metabolic state. While oncogene-targeted therapies tend to cause an increased expression of melanoma antigens, which is triggered by altered metabolic demands and MITF-mediated regulation of mitochondrial biogenesis through PGC1???there is a drastic decrease in the levels of this immune suppressive molecule. Hence, these data suggested that increased immune surveillance may intersect with the effects of targeted therapies. Our preliminary studies demonstrate that oncogenic signaling governs transcriptional regulation of transcriptional regulation of this immune suppressive molecule, and that manipulation of its levels alters tumor growth in vivo, associated with changes in tumor immunogenicity. Furthermore, we demonstrate that heightened expression of this molecule is correlated with poor prognosis in patients who otherwise would be expected to benefit from immune checkpoint therapies. In this proposal, we will perform studies that dissect the molecular mechanisms that control this immune suppressive molecule's expression levels. We will further assess the degree to which this protein modifies the effects of immune checkpoint therapies, and determine if its prospective use might be used to inform clinical decisions. Successful completion of the proposed studies should improve clinical management and propose combinatorial targets for investigation.